Subtilase cytotoxin cleaves newly synthesized BiP and blocks antibody secretion in B lymphocytes
Name
Hu-2009-Subtilase cytotoxin.pdf
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4.4 MB
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Author(s)
Hu, Chih-Chi Andrew
Dougan, Stephanie K.
Winter, Sebastian Virreira
Paton, Adrienne W.
Paton, James C.
Date Issued
October 2009
Journal
Journal of Experimental Medicine
Publisher
Rockefeller University Press
Citation
Chih-Chi, Andrew Hu, et al. (2009). Subtilase cytotoxin cleaves newly sythesized BiP and blocks antibody secretion in B lymphocytes. Journal of experimental medicine 206: 2429-2440. © 2009 Rockefeller University Press
Version
Final published version
Abstract
Shiga-toxigenic Escherichia coli (STEC) use subtilase cytotoxin (SubAB) to interfere with adaptive immunity. Its inhibition of immunoglobulin secretion is both rapid and profound. SubAB favors cleavage of the newly synthesized immunoglobulin heavy chain–binding protein (BiP) to yield a C-terminal fragment that contains BiP’s substrate-binding domain. In the absence of its regulatory nucleotide-binding domain, the SubAB-cleaved C-terminal BiP fragment remains tightly bound to newly synthesized immunoglobulin light chains, resulting in retention of light chains in the endoplasmic reticulum (ER). Immunoglobulins are thus detained in the ER, making impossible the secretion of antibodies by SubAB-treated B cells. The inhibitory effect of SubAB is highly specific for antibody secretion, because other secretory proteins such as IL-6 are released normally from SubAB-treated B cells. Although SubAB also causes BiP cleavage in HepG2 hepatoma cells, (glyco)protein secretion continues unabated in SubAB-exposed HepG2 cells. This specific block in antibody secretion is a novel means of immune evasion for STEC. The differential cleavage of newly synthesized versus "aged" BiP by SubAB in the ER provides insight into the architecture of the ER compartments involved.
Subjects
animals
antibodies, immunology
B-lymphocytes, drug effects
B-lymphocytes, immunology
cell membrane, drug effects
endoplasmic reticulum, drug effects
endoplasmic reticulum, metabolism
escherichia coli proteins, pharmacology
heat-shock proteins, biosynthesis
heat-shock proteins, chemistry
histocompatibility antigens class I, immunology
immunoglobulin M, immunology
immunoglobulin kappa-chains, immunology
interleukin-6, secretion
intracellular space, drug effects
intracellular space, metabolism
mice
models, immunological
peptide fragments, metabolism
protein folding, drug effects
protein transport, drug effects
subtilisins, pharmacology
antibodies
escherichia coli proteins
heat-shock proteins
histocompatibility antigens class I
immunoglobulin M
immunoglobulin kappa-chains
interleukin-6
peptide fragments
molecular chaperone grp78
subtilase cytotoxin, e coli
MIT Department
Massachusetts Institute of Technology. Department of Biology
Whitehead Institute for Biomedical Research
Terms of Use
Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1084/jem.20090782
